Formulations and methods of manufacturing formulations for use in colonic evacuation

ABSTRACT

Formulations and methods of manufacturing formulations for use in colonic evacuation are disclosed herein, in an embodiment, a solid dosage formulation includes an intra-granular fraction intermingled with an extra-granular fraction, wherein the intra-granular fraction includes granules comprising at least one osmotic evacuant agent, at least one antacid, and a first pharmaceutically acceptable excipient component, and wherein the extra-granular fraction includes one or more organic acids, a non-metallic lubricating element, and a second pharmaceutically acceptable excipient component.

RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.14/417,172, filed on Jan. 26, 2015, allowed, which is a 371 nationalstage filing of International Application No.

PCT/IB2013/01640, filed on Jul. 26, 2013, which claims the benefit ofand priority to U.S. Provisional Application Ser. No. 61/676,608, filedon Jul. 27, 2012. The entire contents of the foregoing applications areincorporated by reference in their entireties herein.

BACKGROUND

The advent of colonoscopy brought with it the need for a simplified,routine bowel cleansing protocol or product to achieve a clean colonicmucosa required to detect even small lesions or abnormalities in thebowel Similar requirements exist for colonic surgery.

SUMMARY

Formulations and methods of manufacturing formulations for use incolonic evacuation are disclosed herein.

According to aspects illustrated herein, there is disclosed a soliddosage formulation that includes an intra-granular fraction intermingledwith an extra-granular fraction, wherein the intra-granular fractionincludes granules comprising at least one osmotic evacuant agent, atleast one antacid, and a first pharmaceutically acceptable excipientcomponent, and wherein the extra-granular fraction includes one or moreorganic acids, a non-metallic lubricating element, and a secondpharmaceutically acceptable excipient component.

According to aspects illustrated herein, there is disclosed a method ofevacuating a colon of a patient that includes orally administering tothe patient, within a 24-hour time frame, between 25 and 30 tablets witha liquid, wherein each of the tablets includes an intra-granularfraction intermingled with an extra-granular fraction, wherein theintra-granular fraction includes granules comprising sodium picosulfate,magnesium oxide, simethicone and a first pharmaceutically acceptableexcipient component, wherein the extra-granular fraction includesascorbic acid and a second pharmaceutically acceptable excipientcomponent, and wherein all the tablets combined yield a total dose ofabout 30 mg sodium picosulfate, about 7 g of magnesium oxide, about 15 gof ascorbic acid, and about 100 mg of simethicone. In an embodiment, theformulation requires a minimum ingestion of fluid while avoiding sideeffects of fluid shifts. In an embodiment, the formulation has anoptimal drug release profile and suitable stability to provide adequateshelf life.

According to aspects illustrated herein, there is disclosed a method ofmanufacturing a solid dosage formulation that includes (i) wetgranulating at least one osmotic evacuant agent, at least one antacid,and a first pharmaceutically acceptable excipient component to form anintra-granular granular fraction; (ii) blending the intra-granularfraction obtained from step (i) with elements of an extra-granularfraction comprising one or more organic acids, a non-metalliclubricating element, and a second pharmaceutically acceptable excipientcomponent; and (iii) compressing the blend obtained from step (ii) intotablets.

BRIEF DESCRIPTION OF THE DRAWINGS

The presently disclosed embodiments will be further explained withreference to the attached drawings.

FIG. 1 is a graph showing the release of sodium picosulfate over timefrom formulations of the present disclosure.

FIG. 2 is a bar graph showing the release of sodium picosulfate overtime from formulations of the present disclosure.

While the above-identified drawings set forth presently disclosedembodiments, other embodiments are also contemplated, as noted in thediscussion. This disclosure presents illustrative embodiments by way ofrepresentation and not limitation. Numerous other modifications andembodiments can be devised by those skilled in the art which fall withinthe scope and spirit of the principles of the presently disclosedembodiments.

DETAILED DESCRIPTION

Formulations and methods of manufacturing formulations for use incolonic evacuation are disclosed herein. In an embodiment, a soliddosage formulation includes an intra-granular fraction intermingled withan extra-granular fraction, wherein the intra-granular fraction includesgranules comprising at least one osmotic evacuant agent, at least oneantacid, and a first pharmaceutically acceptable excipient component,and wherein the extra-granular fraction includes one or more organicacids, a non-metallic lubricating element, and a second pharmaceuticallyacceptable excipient component.

As used herein, the term “intra-granular fraction” refers to thosecomponents of a formulation of the present invention that are withingranules.

As used herein, the term “extra-granular fraction” refers to thosecomponents of a formulation of the present invention that are outside ofthe granules. During manufacturing, the extra-granular fraction includesthe ingredients that are added to the intra-granular fractionpost-drying.

In an embodiment, the intra-granular fraction (i.e. granules) may forexample comprise up to 50% of the total weight of the formulation, e.g.from 30% to 50% by weight of the formulation. The at least one osmoticevacuant agent component of the intra-granular fraction may for examplecomprise up to 1% of the total weight of the formulation. The at leastone antacid component of the intra-granular fraction may for examplecomprise up to 20% of the total weight of the formulation. The firstpharmaceutically acceptable excipient component of the intra-granularfraction may for example comprise up to 30% of the total weight of theformulation. The granules of the intra-granular fraction may, forexample, have a size of from 25 microns to 1000 microns. The granules ofthe intra-granular fraction may, for example, have an average size offrom 150 microns to 300 microns.

In an embodiment, the extra-granular fraction may for example compriseup to 50% of the total weight of the formulation. The one or moreorganic acids of the extra-granular fraction may for example comprise upto 40% of the total weight of the formulation. The non-metalliclubricating element of the extra-granular fraction may for examplecomprise up to 3% of the total weight of the formulation. The secondpharmaceutically acceptable excipient component of the extra-granularfraction may for example comprise up to 10% of the total weight of theformulation.

Suitable osmotic evacuant agents include, but are not limited to,sulfate based laxatives and phosphate based laxatives. Examples ofsulfate based laxatives include, but are not limited to, sodiumpicosulfate, sodium sulfate and magnesium sulfate. A mixture of two ormore sulfate based laxatives may be used. Examples of phosphate basedlaxatives include, but are not limited to, sodium dihydrogen phosphate,disodium hydrogen phosphate, sodium biphosphate, sodium acidpyrophosphate, and/or mixtures thereof.

The osmotic evacuant agent may further comprise an antacid selected fromthe group consisting of magnesium oxide, calcium carbonate, magnesiumalginate, magnesium hydroxide, magnesium carbonate, magnesium citrate,magnesium aspartate, and magnesium trisilicate. In an embodiment, theantacid is magnesium oxide. In one embodiment, the osmotic evacuantagent comprises a mixture of sodium picosulfate and magnesium oxide.

In a further embodiment, the sodium picosulfate comprises micronizedsodium picosulfate.

The formulation of the present disclosure may be a tablet. For examplethe tablet may be a compressed tablet, a coated tablet or an explodingtablet. Alternatively, the formulation may comprise a capsule. Examplesinclude a coated capsule or an exploding capsule; a lozenge; or a pill.

The formulation may have a delayed release profile, a slow releaseprofile or a controlled release profile of one or more of the at leastone osmotic evacuant agent; the one or more organic acids; or the atleast one excipient including a non-metallic lubricating agent.

To achieve a delayed release of one or more components of thepharmaceutical composition, it may be formulated with a coating as notedabove. Further, the delayed release of one or more of the components maybe achieved by other formulation methods including multiple layers orcompartments of the solid oral dosage form.

Suitable organic acids include, but are not limited to, ascorbic acid,citric acid, tartaric acid, mixtures of citric acid and ascorbic acid,and mixtures of tartaric acid in combination with ascorbic acid and/orcitric acid.

Typically, the lubricating agent of the formulation comprises a fattyacid ester. For example, the lubricating agent may comprise glycerylbehenate. In an embodiment, Compritol® 888ATO is used as the glycerylbehenate. In another embodiment, the fatty acid ester may result fromone or more of the following fatty acids: caprylic acid, capric acid,lauric acid, myristic acid, palmitic acid, stearic acid, lignocericacid, oleic acid, linoleic acid, erucid acid, linoleic acid, or coconutoil.

The formulation may further include a number of other excipientsincluding a diluent selected from one or a mixture of any one or more ofthe following: mannitol, lactose monohydrate, microcrystalline cellulose(e.g. sold under the trade name Avicel® PH 101), or sorbitol.

The formulation may further include a binder agent. For example theformulation may include polyvinyl pyrrolidone (PVP), including PVP K30;hydroxypropylcellulose, or polyethylene glycol (PEG), including PEG10000 or PEG 4000.

Typically, the formulation also includes a stabilizing agent. Suitablestabilizing agents include, but are not limited to, sodiummetabisulfite, sodium bisulphite and sodium sulfite.

A disintegrant may also be included in the formulation and may includecross linked povidone (crospovidone). Alternatively sodium starchglycolate (SSG) may be used as a disintegrant.

An anti-foaming agent may also be included in the formulation. Suitableanti-foaming agents include, but are not limited to,polydimethylsiloxane, hydrated silica gel, and mixtures ofpolydimethylsiloxane and hydrated silica gel. In one embodiment theanti-foaming agent is simethicone. A further example of an anti-foamingagent is dimethicone.

An anti-adherent element may also be included in the formulation for theintra-granular fraction and for the extra-granular fraction and may bethe same or different and may comprise one or more (known) substances orcompounds which (in appropriate amounts) are capable of reducing thestickiness of the composition or formulation, for example, inhibitingadherence to metal surfaces. Suitable anti-adherent type materialsinclude, but are not limited to, talc and silicon-containing compoundssuch as colloidal silicon dioxide (e.g. sold under the trade nameAerosil®) as well as mixtures thereof.

Generally, the formulation may be orally administered with any liquidsuitable for ingestion. Preferably, water, mineral water, glucose-freemineral water, glucose-free cordial or glucose-free soft drink are used.The volume of liquid consumed with the formulation varies from 250 mL to2,000 mL, for example, 250 mL to 1,500 mL or 500 mL to 1,500 mL or 2,000mL.

Generally, the formulation is orally administered to a patient over aperiod of time. The formulation is usually prepared as a number oftablets or capsules which are taken over a period of time.

A typical total dose of the osmotic evacuant agent is in the range offrom 1 to 100 mg, preferably 5 to 50 mg, preferably 10 to 40 mg, morepreferably 30 mg. In one embodiment, the evacuant agent in such a dosageregimen comprises a sulfate based laxative.

A typical example of a treatment regimen involves the preparation of theformulation into approximately 30 tablets or capsules. Approximately 5tablets or capsules are ingested with approximately one glass of liquidover a period of 1 second to 20 minutes, typically 5 seconds to 5minutes, typically 10 seconds to 3 minutes, typically 30 seconds to 15minutes, typically 15 minutes to 20 minutes, typically 1 minute to 10minutes, more typically 1 minute to 6 minutes. A further 5 tablets orcapsules are ingested with approximately one glass of liquid over 10seconds to 20 minutes, typically 30 seconds to 15 minutes, or 15 minutesto 20 minutes, typically 1 minute to 10 minutes, more typically 1 minuteto 6 minutes after approximately 20 minutes to 2.5 hours, typically 25minutes to 1 hour, more typically 30 to 40 minutes. This regimen isrepeated until all the tablets or capsules have been ingested.

A typical example of a treatment regimen of the invention involves thepreparation of the formulation into approximately 5 to 40 tablets orcapsules. Approximately one fifth of the tablets or capsules arcingested with approximately one glass of liquid over a period of 1second to 20 minutes, typically 5 seconds to 5 minutes, typically 10seconds to 3 minutes, typically 30 seconds to 15 minutes, typically 15minutes to 20 minutes, typically 1 minute to 10 minutes, more typically1 minute to 6 minutes. A further one fifth of the tablets or capsulesare ingested with approximately one glass of liquid over 10 seconds to20 minutes, typically 30 seconds to 15 minutes, or 15 minutes to 20minutes, typically 1 minute to 10 minutes, more typically 1 minute to 6minutes after approximately 20 minutes to 2.5 hours, typically 25minutes to 1 hour, more typically 30 to 40 minutes. This regimen isrepeated until all the tablets or capsules have been ingested.

Generally, the typical examples of the treatment regimen take 2 to 15hours, for example, 2 to 12 hours or 2.5 to 15 hours, preferably 2.5 to6.5 hours, more preferably 2 to 4.5 hours, even more typically 2 to 3.5hours.

If the treatment regimen is administered in two parts, there is usuallya difference of 4 to 16 hours, typically 4 to 12 hours, preferably 4 to8 hours, more preferably 4 to 6 hours, between the administration of thefirst treatment regimen and the administration of the second treatmentregimen.

The formulations of the present disclosure are also useful in thetreatment of certain gastrointestinal conditions such as small bowelbacterial overgrowth and irritable bowel syndrome as well as useful intreating acute or chronic bacterial bowel infections, for example,infection of the bowel with one or more bacteria including Campylobacterjejuni, Yersinia enterocolitica, Clostridium difficile, Clyptosporidiumisospora belli. The formulation of the present disclosure can also beused in the treatment of fungal or viral infections in the bowel. Theosmotic colonic evacuant of the present invention can also be used inthe treatment of chronic inflammatory bowel disease such as Crohn'sdisease or ulcerative colitis.

In one embodiment the formulation may be produced by granulation. Thegranulation steps may include dry granulation. Alternatively, thegranulation steps may include wet granulation. The formulation includesan intra-granular fraction intermingled with an extra- granularfraction. Typically, the at least one osmotic evacuant agent isgranulated with one or more excipients and dried to provide an initialgranulation mixture. As a separate step, the one or more organic acid isadded to the initial granulation mixture to provide a second mixture. Asa final step one or more lubricating agents may be added to the secondmixture and the formulation mixed for a pre-determined time period.

The formulation may further comprise one or more layers or compartments.In this embodiment it is envisaged that the at least one osmoticevacuant agent includes a compound having metallic ions and wherein thecompound having metallic ions is in a different layer or compartment tothat containing the one or more organic acid. For example, if the atleast one osmotic evacuant agent includes magnesium oxide, theformulation in solid dosage form would include the magnesium oxide in aseparate layer or compartment to the acid. In an embodiment whereascorbic acid is present, such a physical separation would significantlyreduce the degradation of the acid in the presence of metallic cations.

The solid dosage formulation may comprise a coating layer to relativelydelay dissolution beyond the mouth of a patient. A suitable coatingagent may include PVA, TiO2, talc, lecithin (soy), and xantham gum (e.g.sold under the name Opadry® AMB White). Further, the coating agent mayinclude PVA, polyethylene glycol and talc (sold under the trade nameOpadry® II Clear). The coating layer may further include methylmethacrylate and diethylaminoethyl methacrylate copolymer. An example ofsuitable lubricants is sold under the trade name Kollicoat® and thevarious compositions are herein incorporated as examples.

EXAMPLES

With aspects of the present formulations and methods now being generallydescribed, these will be more readily understood by reference to thefollowing examples, which are included merely for purposes ofillustration of certain features and embodiments of the presentformulations and methods and are not intended to be limiting. Table 1lists the actives and excipients used in the formulation developmentstudies:

TABLE 1 Material Trade Name Supplier Sodium picosulfate (micronized) N/ACambrex Simethicone LVA N/A Dow Corning Simethicone for DC N/A SPIPharma Magnesium oxide (heavy) N/A Intermag Magnesium oxide (granular)N/A Intermag EC coated Ascorbic acid N/A 3501-W01 FC coated Ascorbicacid N/A DSM Sodium ascorbate N/A Sigma Mannitol (Pearlitol 200 SD)Perlitol ® 200SD Roquette Lactose monohydrate Pharmatose ® 200M DMVFonterra Microcrystalline Cellulose Avicel ® PH-101 FMC MicrocrystallineCellulose Avicel ® PH-102 FMC Polyvinyl Pyrrolidone K30 Povidone K30BASF Prosolv Easy Tab JRS Pharma Hydroxypropylcellulose (HPC) Klucel ®Hercules Polyethylene glycol 10000 N/A Clariant Polyethylene glycol 4000N/A Prolabo Citric acid anhydrous N/A Sigma Tartaric acid N/A FlukaSodium metabisulphite (97%) N/A Alfa Aesar Sodium bisulphite (sodium N/AAlfa Aesar hydrosulphite) Sodium sulphite N/A Alfa Aesar Sodium starchhlycollate Explotab ® JRS Crospovidone Polyplasdone ® XL ISP MagnesiumStearate N/A Riedel de Haen Glyceryl behenate Compritol ® 888 ATOGattefossé Silicon Dioxide Aerosil ® 200 In house sample HMPC CapsulesN/A Qualicaps Sodium Lauryl Sulphate N/A VWR OPADRY AMB white N/AColourcon OPADRY II clear N/A Colourcon

Example 1 Formulation Studies

Formulation studies were undertaken to compare powder formulations incapsules (size 0) and tableting studies. Granulation was used as adensification method and various methods such as aqueous, melt and drygranulation were studied. Various changes were made to the formulationsand different prototypes prepared. Both the powder blends and thegranulated formulations were examined for tapped density, powder flow,compressibility index, moisture content and sieve analysis.

Dry Powder Blends

Powder blends were prepared as follows: the required amounts of activeand excipients were dispensed into suitable containers. To a high shearmixer the following were added in order: ascorbic acid (half), MgO(half), SSG, sodium picosulfate, binder, simethicone, MgO (half) andascorbic acid (half). This mixture was mixed for a predetermined timeperiod, for example, 2 mins at high speed with the mixer shaken/tiltedoccasionally. Small portions of the powder blend were transferred into ajacketed vessel that was preheated at a selected temperature, forexample, 62° C.-65° C. and mixed with a spatula until granules wereformed. This was repeated until all the powder blend was granulated. Thegranules were emptied into wide opened glass beakers and cooled at roomtemperature overnight. The granules were sieved, weighed and theextra-granular excipients added accordingly. The resulting mixture wasagitated and stirred for a pre-determined time period, for example 10mins. Lubricant was then added and mixed for a pre-determined timeperiod, for example 1 minute.

Melt Granulation

Melt agglomeration is a process by which the solid fine particles arebound together into agglomerates, by agitation, kneading, and layering,in the presence of a molten binding liquid. Dry agglomerates areobtained as the molten binding liquid solidifies on cooling. The mainadvantages of the procedure are that neither solvent nor water is usedin this process, hence the procedure is suitable for molecules thatdissociates in aqueous media. Fewer processing steps are needed thustime consuming drying steps are eliminated. Formulations were preparedusing a jacketed vessel and two different hydrophilic meltable binders,PEG 10,000 and PEG 4,000. Both meltable binders were milled down using aKenwood mixer as they were relatively large flakes. Two methods wereused to add the binder to the formulation:

Method A: The binder was added directly to the formulation blends andmixed either using the low shear mixer (Kenwood) or the Turbula mixer.Powder blends were prepared as follows:p 1. The required amounts of active and excipients were dispensed intosuitable containers.2. The active was then sandwiched between diluent in a high shear mixer(Kenwood) by adding in the following order: ascorbic acid (half), MgO(half), SSG, sodium picosulfate, binder, simethicone, MgO (half) andascorbic acid (half).3. Mixed for 2 mins at high speed with the mixer shaken/tiltedoccasionally.4. Transfer small portions (40g) of the powder blend in the jacketedvessel preheated at 62-65° C. mixed with a spatula until granules wereformed. This was repeated until all the powder blend was granulated.5. Emptied the granules in wide opened glass beakers and leave to cooldown at room temperature overnight.6. Sieve, weight and add accordingly the extra-granular excipients.7. Mix with Turbula mixer for 10 mins at 49 rpm.8. Add magnesium stearate and mix just for 1 minute at 49 rpm.Method B: A single batch of the formulation prepared by hot meltgranulation was also prepared by pre-melting the binder in the jacketedvessel, to investigate the effect of the method of the preparation onthe flow properties. The other steps were as above.

As the theoretical fill weight for the melt granulation formulation washigher compared to the dry powder blend, it was estimated thatformulations with a tapped density of 1.25-1.32 g/ml will be required inorder to be filled into size 0 or 0el. Several formulations wereprepared where various factors were investigated such as: usingdifferent amount and grades of PEG, using different grades of MgO,different mixing time and different temperature for mixing.

As the amount of the meltable binder increased, no significant change inthe tapped density was observed. The highest tapped density valueachieved was for a formulation containing 10% w/w PEG10,000 mixed for 30mins at 65° C. Percentages lower than 10% for

PEG, might give slightly higher tapped density values to aid packing.Formulations prepared with the same composition but using differentgrade of MgO (granular and heavy) indicated that a higher tapped densityvalue can be achieved when granular MgO is used. The Carr's index wasbetween 13-21%, suggesting that good powder flow was achieved.Formulations prepared with different grade of PEG, gave similar valuesfor the tapped density, but still not high enough to ensure the targetfill weight could be achieved. Generally all formulations prepared byhot melt granulation had lower tapped density values than the desiredformulation, suggesting that it will be difficult to achieve the targetfill weight into a size O or Oel.

Using caplet tooling, a tablet was created. Various settings of thetabletting machine were used but the smallest tablets prepared by handwere ˜1.1 g (target weigh was 860 mg/ caplet for 30 units required).Hence it was decided to increase the fill weight of the caplets andreduce the number of caplets required to deliver the target doses (20caplets rather than 30). A number of caplets were manually producedusing two different machine setting to obtain different hardness and thedata indicated that the caplets were uniform in terms of weight andgeneral dimensions. The softer caplets showed a longer disintegrationtime of just under 14 mins. Hence more super disintegrant will berequired in this formulation to reduce the disintegration time. Further,the caplets showed also a change in colour (mottling effect) which mightbe due to the degradation of one of the excipients during granulation ortab letting.

Direct Compression

A formulation blend was prepared by adding ProSolve® Easy Tab (acommercially available blend containing, MCC 102, SiO₂, SSG and sodiumstearyl fumarate) and simethicone suitable for direct compression. Thetheoretical fill weight was increased to allow dosing 24 caplets. Theformulation was further optimized by adding 5% Klucel®, Mannitol andincreased level of super disintegrant. Caplets were produced inautomatic mode using three different settings and results for thetabletting indicated that caplets produced by direct compression wereuniform and the hardness varies from 25N (softest) to 78N (hardest), theincrease in SSG level reduced the disintegration time, and that all 3types of caplets, with various hardness's, failed the friability test.The results indicated that this formulation blend was not suitable fortabletting.

Dry Granulation (Slugging)

In a dry granulation process the powder mixture is compressed withoutthe use of heat and solvent. The two basic procedures are to form acompact of material by compression and then to mill the compact toobtain a granules. Two methods are used for dry granulation and sluggingis one of these methods. The more widely used method is rollercompaction. Granulation by slugging is the process of compressing drypowder of tablet formulation with a tablet press having a die cavitylarge enough in diameter to fill quickly. Once slugs are produced theyare reduced to appropriate granule size for final compression bygrinding and sieving or milling. Powder blends were prepared as follows:

1. Required amount of active and excipients were dispensed into suitablecontainers.2. Preblend the simethicone with a portion of Avicel® in the high shearblender (Kenwood)3. The active was then sandwiched between the excipients in Turbulamixer by adding in the following order: ascorbic acid (half), MgO(half), SSG, sodium picosulfate, binder, simethicone/ Avicel® mixturefrom point 2, MgO (half) and ascorbic acid (half)4. Mix for 10 mins using the Turbula mixer at 49 rpm.5. Tablet the formulation blend using 15 mm round flat tooling in orderto obtain soft tablets.6. Mill the soft tablets in the mortar and pestles and sieve through 600gm sieve. Record the weight.7. Add in sandwich mode the granules and the extra granular excipientsand mix in Turbula mixer for 10 mins at 49 rpm.8. Add magnesium stearate and mix for a further 1 minute at 49 rpm.

Preliminary data on the formulations indicated that a higher amount ofsuper disintegrant was required to aid disintegration. Hence a newformulation was manufactured where:

-   -   Simethicone suspension was replaced with simethicone for direct        compression to improve uniformity within the blend,    -   Avicel® PH-101 was replaced with grade PH-102 to improve        potentially the compressibility of the powder and add increased        the level of super disintegrant.

A formulation was tabletted in automatic mode using 2 different machinesettings in order to produce caplets with 1000 mg theoretical weight(weight corresponding to 30 caplets required for dosing). Caplets withincreased weight were also produced at the hardest setting possible, inorder to reduce the number of caplets required for administration. Dataindicated that:

-   -   Caplets produced were generally uniform and the hardness varied        from 61 N (softest) to 99 N (hardest).    -   Friability tests were performed for all types of caplets. Both        sets of caplets failed the friability test as caplets split into        halves (delaminate/capping) suggesting that the excipients do        not bind well together in the formulations investigated).

These indicated that different types and higher levels of excipientssuitable for direct compression were needed it to aid tableting.

Wet Granulation

Wet granulation involves addition of a liquid solution (with or withoutbinder) to powders, to form a wet mass. Typically granules are formed bybinding the powder together with help from an adhesive. In the pre-mixstep the powders to be granulated and powdered binder are added andmixed prior to the introduction of the aqueous solution. In the wetmassing step the components are massed to a predetermined end point. Inthe drying step the wet mass is dried to a predetermined end point,commonly measured with a test called the loss on drying (LOD). The driedgranules are then milled to reduce the size of any caked material into astandardized particle size distribution. Then the final blend isprepared by adding the extra granular excipients, and lubricated. Blendswere prepared as follows:

1. Required amount of active and excipients were dispensed into suitablecontainers.2. Weight deionized water into a separate container.3. Place all excipients into the high shear mixer and mix them at highspeed for 5 mins.4. Add water gradually and mix continuously until granules were formed.5. Empty the granules and spread thinly in a tray to dry out either atroom temperature (over week-end) or in the oven at −35-40 ° C.6. Perform moisture analysis to assess the end time point for drying.7. Sieve, weigh, add accordingly the extra granular excipients and mixwith Turbula mixer for 10 mins at 49 rpm. (sieve analysis was performedfor optimized formulations only)8. Add magnesium stearate and mix just for 1 minute at 49 rpm.

A formulation was tabletted manually using a 19×9 mm caplet toolingusing three different machine settings to generate caplets withdifferent hardness'. The caplets were uniform in weight and physicalcharacterization but had a high disintegration time (more than 15 minsfor the softest caplets). This suggested that the level of the superdisintegrant needed to be increased to reduce the disintegration time tounder 15 mins. Thus, a new formulation blend was prepared where lactosewas replaced with mannitol (due to a potential Maillard reaction betweenNH group from sodium picosulfate and lactose) and super disintegrant(SSG) level was increased to improve hardness and disintegration time.Caplets were produced in automatic mode using three different machinesetting and the results are shown below:

-   -   Caplets produced were uniform in terms of weight and the        hardness varies from 64 N (softest) to 133 N (hardest).    -   The increase in SSG level reduced the disintegration time.    -   The softest caplets, failed the friability test. The other 2        settings produce caplets which passed both the disintegration        and friability test. Conventional compressed tablets that losses        less than 0.5% to 1% of weight are considered acceptable.

Following the success in producing caplets (with 1275 mg theoreticalweight required for 30 caplets) with good disintegration, friability anddissolution profile, new caplets were produced with increasedtheoretical weight (1593 mg) in order to reduce the number of capletsadministered (24 caplets/patient). Caplets that passed bothdisintegration and friability test were prepared. However the capletswere thicker and potentially difficult to swallow.

Example 2 Stability Studies

Two formulations were prepared and analyzed, one dry powder blend filledinto size Del and one formulation prepared by wet granulation as acaplet.

For the initial time point:

-   -   The assay, content uniformity, and dissolution results were        variable for the dry blend filled into capsule indicating a        non-homogeneous blend of the sodium picosulfate. The water        content observed for the capsule formulation was higher than for        the tablet formulation.    -   The assay, content uniformity, and dissolution results were        consistent for the wet granulation tablet indicating a        homogeneous blend of the sodium picosulfate. Also no impurities        were observed in this formulation.

For T=1 Months

-   -   The assay, content uniformity, and dissolution results remained        variable for the dry blend capsule indicating a non-homogeneous        blend of the sodium picosulfate. The water content observed had        increased in comparison to the initial analysis, and remained        higher than for the tablet formulation.    -   The assay, content uniformity, and dissolution results were        consistent, and comparable to the initial data, for the wet        granulation tablet indicating a homogeneous blend of the sodium        picosulfate. The water content observed was consistent in        comparison to the initial analysis, and remained to be lower        than for the capsule formulation. Also, there was an increase in        impurities seen.

Both formulations changed colour at 40° C/75% RH even at T=2 weeksindicating degradation process. It was believed that the browning effectwas due to the ascorbic acid degradation in presence of high moistureand on heat.

To confirm which combination of ingredients lead to changing colour ofthe formulations, several binary and tertiary mixtures of sodiumpicosulfate, ascorbic acid and citric acid were prepare with theindividual excipients present in the formulation. Additional componentswere added to investigate the effect of adding some stabilizers to theoriginal formulation to prevent browning effect. Samples were also placeinto three types of containers, closed, opened, and in DUMA bottles withdesiccant, to study the effect of the moisture ingress.

Example 3 Excipient Compatibility Studies

Excipient compatibility studies with all excipients against Napicosulfate and ascorbic acid were carried out. Antioxidants like Nameta-bisulphite, Na bisulphite and Na sulphite were added. Further, thestudy was carried out to determine if citric acid helped stabilize thecolour change of ascorbic acid. Samples were assessed at 1 week, 2weeks, 4 weeks and at 8 weeks.

Tertiary Mixtures with Components (250 mg MgO +500mg AA+25 mg Sulphites(or 100 mg Acids)

MgO+ascorbic acid+Na meta-sulphite

MgO+ascorbic acid+Na bisulphite

MgO+ascorbic acid+Na sulphite

MgO+ascorbic acid+citric acid

MgO+ascorbic acid+tartaric acid

MgO+sodium ascorbate+Na meta-sulphite

MgO+sodium ascorbate+Na bisulphite

MgO+sodium ascorbate+Na sulphite

MgO+sodium ascorbate+citric acid

MgO+sodium ascorbate+tartaric acid

Quaternary Mixtures with Components ((250 mg MgO+500 mg AA+20 mg NaP+25Sulphites (or 100 mg acids)

MgO+Na picosulfate+ascorbic acid+Na meta-sulphite

MgO+Na picosulfate+ascorbic acid+Na bisulphite

MgO+Na picosulfate+ascorbic acid+Na sulphite

MgO+Na picosulfate+ascorbic acid+citric acid

MgO+Na Picosulfate+ascorbic acid+tartaric acid

Binary, tertiary and quaternary mixtures of the API and excipients atvarious ratios were prepared as follows:

1. Weigh approximately required amount of excipient into a weighingboat.2. Add approximately half of the excipient quantity into a container.3. Weigh the API/ascorbic acid/citric acid into the container.4. Manually mix the blend and with the aid of the micro-spatula break-upany agglomerates.5. Blend the mixture in a Turbula mixer for 15 minutes at 49 rpm.6. After mixing all samples were assumed to be homogenous, and weredispensed in suitable containers, then placed on stability storage. Pulltimes: 1, 2, 4 and 8 weeks.

Excipients compatibility study showed that:

-   -   Up to 8 weeks, binary mixtures with ascorbic acid changed colour        in presence of excipients and stabilizers containing metallic        cations. Some changes were noted also in opened containers also.    -   No changes in colour was observed for binary and tertiary        mixtures when kept in DUMA bottles with desiccant cap suggesting        that the final product will have to be protected from moisture        ingress.

The excipient compatibility study of ascorbic acid with variousexcipients indicated that ascorbic acid degrades in the presence ofmetallic cations (such as: Cu2+, Fe3+, Zn2+). As a result, two changeswere made to the formulation blend prepared by wet granulation. Firstly,the sodium starch glycollate was replaced with crospovidone XL, andsecondly the magnesium stearate was replaced with Compritol 888ATO. Alsothe Avicel® PH101 was added split 50/50 intra-granular andextra-granular.

Example 4 Optimization of wet granulated formulation blend

Further optimization studies were carried out for the wet granulatedformulation. To reduce ascorbic acid degradation in the presence ofmetallic cations, some excipients of the formulation containing metalliccations were replaced with non-metallic excipients. Additionally, andwith a view to further minimising ascorbic acid degradation, the stepsof granulation were modified and the effects of having a coatingreviewed.

Three wet granulation formulations were prepared, where Avicel was addedi) intra granular, ii) split intra granular and extra granular and iii)extra granular only. All three batches were prepared as follows:

1. Required amount of active and excipients were dispensed into suitablecontainers.2. Weight deionized water into a separate container.3. Place all excipients into the high shear mixer and mix at high speedfor 2 mins.4. Add water gradually and mix continuously until granules were formed.Record the amount of water used and the mixing time.5. Empty the granules and spread thinly in a tray to dry out either atroom temperature 3 (over week-end) or in the oven at −35-40 ° C.6. Perform moisture analysis to assess the end time point for drying.7. Collect approximately 100 g of the dry granules and perform sieveanalysis.8. Add accordingly the extra granular excipients and mix with Turbulamixer for 10 rains at

49 rpm.

Sieve analysis indicated that:

-   -   Formulations containing Avicel as intra-granular excipient (100        or 50%) have a smaller median particle diameter compared to the        formulation containing no Avicel intra-granular. This suggests        that the formulations containing some Avicel intra-granular are        more suitable for further studies, as bigger granules might lead        to segregation caused by particle size difference between        materials in a bulk blend.    -   Powder flow properties indicated that all three formulations        prepared had good powder flow properties.

Example 5 Formulations

Formulation A was prepared by wet granulation at −1.5kg scale, yieldingenough batch to prepare between 25 and 30 tablets, wherein all thetablets combined yield a total dose of about 30 mg sodium picosulfate,about 7 g of magnesium oxide, about 15 g of ascorbic acid, and about 100mg of simethicone. Table 3 lists the components of Formulation A:

TABLE 3 Intra-granular Weight Weight Components (mg) (mg) Wt/unit % w/wWeight (g) Mannitol 7200 7200.00 240.00 18.82 301.17 Magnesium Oxide7000 7000.00 233.33 13.30 292.81 granules Sodium picusulfate 30 31.171.04 0.08 1.30 (micronized) Simethicone for DC 100 147.71 4.92 0.39 6.18Crospovidone 940 940.00 31.33 2.46 39.32 PVP K30 1800 1800.00 60.00 4.7175.29 Microcrystalline 1893 1893.00 63.10 4.95 79.18 Cellulose-50%(Avicel ® PH101) The above constituents were granulated and dried thensieved and the following added accordinly: Extra-granular ComponentsMicrocrystalline 1893 1893.00 63.10 4.95 79.18 Cellulose-50% (Avicel ®PH101) Ascorbic acid 15000 15151.52 505.05 39.61 633.78 Crospovidone 940940.00 31.33 2.46 39.32 Aerosil ® 105 105.00 3.50 0.27 4.39 The aboveconstituents were granulated and dried then sieved and the followingadded accordingly: Compritol ® 888ATO 1149 1149.00 38.30 3.00 48.06TOTAL 38157 38250.40 1275.01 100.00 1600.00

Median Particle Diameter for the intra-granular granules of FormulationA was 289 microns.

Formulation B was prepared by wet granulation at—1.5kg scale, yieldingenough batch to prepare between 25 and 30 tablets, wherein all thetablets combined yield a total dose of about 30 mg sodium picosulfate,about 7 g of magnesium oxide, about 15 g of ascorbic acid, and about 100mg of simethicone. Table 4 lists the components of Formulation B:

TABLE 4 Weight % Weight Intra-granular Components Weight (mg) (mg)Wt/unit w/w (g) Mannitol 6314.5 6314.5 210.48 16.51 247.63 MagnesiumOxide granules 7000 7000.00 233.33 18.30 274.51 Sodium picosulfate 3031.17 1.04 0.08 1.22 (micronized) Simethicone for DC 100 147.71 4.920.39 5.79 Crospovidone 1925 1925.00 64.17 5.03 75.49 PVP K30 11001100.00 36.67 2.88 43.14 Microcrystalline Cellulose- 1700 1700.00 56.674.44 66.67 50% (Avicel ® PH101) The above constituents were granulatedand dried then sieved and the following added accordinyly:Extra-granular Components Microcrystalline Cellulose- 1700 1700.00 56.674.44 66.67 50% (Avicel ® PH101) Ascorbic acid 15000 15151.52 505.0539.61 594.18 Crospovidone 1925 1925.00 64.17 5.03 75.49 Aerosil ® 105105.00 3.50 0.27 4.12 The above constituents were granulated and driedthan sieved and the following added accordinly: Compritole 888ATO 11501150.00 38.33 3.01 45.10 TOTAL 38157 38249.90 1275.00 100.00 1500.00

Median Particle Diameter for the intra-granular granules of FormulationB was 175 microns.

The blend and content uniformity of uncoated batches of Formulation Awere found to be consistent and to a high standard, see Table 5 below.

TABLE 5 Uncoated Tablets Blend uniformity Content uniformity Batch %Assay % Assay Min 83.41 86.74 Max 108.61 100.42 Avg 90.71 91.44 S.D 7.954.62 % RSD 8.77 5.05

The appearances of the tablets were initially smooth, plain colour onall sides and free from any spots. Further studies to compare uncoatedtablets of Formulation A with coated tablets were performed. Tabletcharacteristics of uncoated batches of Formulation A are provided belowin Table 6:

TABLE 6 Uncoated Tablets Weight Length Thickness Width HardnessFriability Disintegration Tablet (g) (mm) (mm) (mm) (N) test timeAverage 1.28 19.24 6.83 9.12 106.40 PASSED PASSED Std 0.01 0.09 0.060.01 2.15 (0.16%) (5-6 MIN) % RSD 0.74 0.49 0.86 0.15 2.02

Further samples of Formulation A using different coatings and coatingparameters were prepared. Examples of the coatings used in the studiesare listed in Table 7:

TABLE 7 Chemical Coating Composition of Solution Coating Weight CoatingType Coating layer Concentration Coating parameters gain Opadry ® PVA,TiO2, talc, 20% w/w Time 37 min Temp AMB White lecithin(soy), 46-50° C.Xanthan gum Opadry ® II PVA, polyethylene 20% w/w Time 19 min Temp Clearglycol, talc 46-50° C.

The coated formulations of Formulation A were: Coated Formulation (i)=Formulation A coated using Opadry® AMB White and stored at 25° C/60%R1-1;

Coated Formulation (ii) =Formulation A coated using Opadry® AMB Whiteand stored at 40° C/75% R1-1

Coated Formulation (iii) =Formulation A coated using Opadry® II clear at40° C/75% R1-1.

A stability study of the coated tablets was undertaken and the followingresults observed:

Appearance of the Tablet Initially and After 4 Weeks.

A) Initial appearance:

Coated Formulation (i)

oblong, smooth, plain white colour on both sides, free from any spots

Coated Formulation (ii)

oblong, smooth, plain white colour on both sides, free from any spots

Coated Formulation (iii)

not tested

B) Appearance at 4 weeks:

Coated Formulation (i)

oblong, smooth, plain white colour on both sides, free from any spots

Coated Formulation (ii)

oblong, smooth, plain white colour on both sides, free from any spots

Coated Formulation (iii)

oblong, smooth, pale yellow colour on both sides

Moisture Content of the Tablets After 4 Weeks.

Table 8 shows the % Water Content by Karl Fischer (T=4 weeks) for threedifferent batches of each of coated formulations (i), (ii) and (iii).

TABLE 8 Coated Formulation Coated Formulation Coated Formulation Batch(i) (ii) (iii) 1 6.01 7.08 6.15 2 6.52 6.87 6.11 3 5.94 6.96 6.34 Mean6.15 6.97 6.20

Table 9 shows the Moisture Content by Karl Fischer (comparative data ofmean % water content of each coated formulation at T=0, 2 weeks, 4weeks, 8 weeks, 12 weeks and 16 weeks).

TABLE 9 Formulation Initial 2 weeks 4 weeks 8 weeks 12 weeks 16 weeks(i) 7.67 7.78 6.15 6.60 6.48 6.49 (ii) 7.67 7.60 6.97 6.59 6.76 7.68

Drug Release

Formulations (i) and (ii) were further tested for drug release of thesodium picosulfate over time. Table 10 lists the dissolution parameters

TABLE 10 Dissolution Parameters Media 1% SLS (Sodium Lauryl Sulphate) inde-ionised water RPM 100 (150 from 60 to 90 minutes) Bath temperature3.75 ± 0.5° C. Volume 500 ml Apparatus USP-11 (paddle) Time points 0,10, 20, 30, 45, 60 and 90 mins

Percentage drug release of sodium picosulfate in formulations (i) and(ii) over time is shown in FIG. 1 and FIG. 2.

Summary

At 16 weeks, there was no change in the physical appearance of thetablets of formulation (ii) compared to initial samples. There was alsono significant variation observed in the moisture level from the initialsamples to the 16 week samples.

The dissolution data showed that 80% drug release was achieved after 30minutes for the tablet of formulation (i). A delay in the release ofsodium picosulfate was observed for formulation (ii), that is, when keptat 40° C. at 75% RH.

The formulation of this disclosure provided a stable tablet form with nosigns of degradation at 16 weeks and which delivered an optimal drugrelease profile.

All patents, patent applications, and published references cited hereinare hereby incorporated by reference in their entirety. It will beappreciated by persons skilled in the art that numerous variationsand/or modifications may be made to the above-described embodiments,without departing from the broad general scope of the presentdisclosure. The present embodiments are, therefore, to be considered inall respects as illustrative and not restrictive. Various presentlyunforseen or unanticipated alternatives, modifications, variations, orimprovements therein may be subsequently made by those skilled in theart which are also intended to be encompassed by the following claims.

1.-24. (canceled)
 25. A 24-hour supply of pharmaceutical tabletscomprising: at least 25 tablets, wherein each of the at least 25 tabletscomprises an intra-granular fraction combined with an extra-granularfraction, and a coating layer sufficiently designed to delay dissolutionof the tablet beyond the mouth of the patient, wherein theintra-granular fraction includes granules comprising micronized sodiumpicosulfate, microcrystalline cellulose, magnesium oxide, andcrospovidone, wherein the intra-granular fraction excludes sodium starchglycolate, wherein the extra-granular fraction includes one or moreorganic acids, microcrystalline cellulose, and crospovidone, and whereinthe extra-granular fraction excludes sodium starch glycolate andmagnesium stearate, wherein the organic acid is one of ascorbic acid,citric acid, tartaric acid, or combinations thereof.
 26. The 24-hoursupply of pharmaceutical tablets of claim 25, wherein the at least 25tablets are contained within a bottle.
 27. The 24-hour supply ofpharmaceutical tablets of claim 25, wherein the intra-granular fractionof each tablet comprises about 50% of the total weight of theformulation, and wherein the extra-granular fraction of each tabletcomprises about 50% of the total weight of the formulation.
 28. The24-hour supply of pharmaceutical tablets of claim 25, wherein the atleast one organic acid in each tablet is ascorbic acid.
 29. The 24-hoursupply of pharmaceutical tablets of claim 25, wherein each tabletfurther comprises silicon dioxide.
 30. The 24-hour supply ofpharmaceutical tablets of claim 25, comprising 30 tablets.
 31. A methodof evacuating a colon of a patient comprising orally administering tothe patient, within a 24-hour time frame, all the tablets of claim 25.32. The method of claim 31, wherein all the tablets are administeredwith a liquid.
 33. The method of claim 32, wherein the liquid isselected from the group consisting of water, mineral water, glucose-freemineral water, glucose-free cordial, and glucose-free soft drink.
 34. Amethod of treating small bowel bacterial overgrowth in a patient in needof such treatment comprising orally administering to the patient, withina 24-hour time frame, all the tablets of claim
 25. 35. A method oftreating irritable bowel syndrome in a patient in need of such treatmentcomprising orally administering to the patient, within a 24-hour timeframe, all the tablets of claim
 25. 36. A bowel cleansing productcomprising: a container having at least 25 tablets, wherein each of theat least 25 tablets comprises an intra-granular fraction combined withan extra-granular fraction, and a coating layer sufficiently designed todelay dissolution of the tablet beyond the mouth of the patient, whereinthe intra-granular fraction includes granules comprising micronizedsodium picosulfate, microcrystalline cellulose, magnesium oxide, andcrospovidone, wherein the intra-granular fraction excludes sodium starchglycolate, wherein the extra-granular fraction includes one or moreorganic acids, microcrystalline cellulose, and crospovidone, and whereinthe extra-granular fraction excludes sodium starch glycolate andmagnesium stearate, and wherein the organic acid is one of ascorbicacid, citric acid, tartaric acid, or combinations thereof.
 37. The bowelcleansing product of claim 36, wherein the container is a bottle. 38.The bowel cleansing product of claim 36, wherein the intra-granularfraction of each tablet comprises about 50% of the total weight of theformulation, and wherein the extra-granular fraction of each tabletcomprises about 50% of the total weight of the formulation.
 39. Thebowel cleansing product of claim 36, wherein the at least one organicacid in each tablet is ascorbic acid.
 40. The bowel cleansing product ofclaim 36, wherein each tablet further comprises silicon dioxide.
 41. Thebowel cleansing product of claim 36, comprising 30 tablets.
 42. A methodof evacuating a colon of a patient comprising orally administering tothe patient, within a 24-hour time frame, all the tablets of claim 36.43. The method of claim 42, wherein all the tablets are administeredwith a liquid.
 44. The method of claim 43, wherein the liquid isselected from the group consisting of water, mineral water, glucose-freemineral water, glucose-free cordial, and glucose-free soft drink.